Treatment of Vascular Anomalies With Sirolimus: An Updated Comprehensive Review

Sirolimus, an mTOR inhibitor, has transformed the management of complex slow- flow vascular malformations (VAMs), particularly those driven by PI3K/AKT/mTOR pathway activation. Evidence from prospective trials and real- world cohorts supports its use in venous, lymphatic and combined malformations, as well as in PIK3CA- related overgrowth spectrum (PROS) and PTEN hamartoma tumor syndrome (PHTS). However, sirolimus shows poor or absent benefit in fast- flow lesions such as arteriovenous malformations (AVMs).

This narrative review of the recent literature (2020- 2025) was performed using PubMed, focusing on molecular mechanisms, clinical efficacy, safety, quality of life, therapeutic drug monitoring (TDM) and cost- utility of sirolimus in vascular anomalies.

Sirolimus demonstrates high response rates in slow- flow malformations, with partial responses in approximately 60-85%60-85% of patients and clinically meaningful improvements in health- related quality of life (HRQoL). Lower trough levels (4- 10 ng/mL) provide comparable efficacy with reduced toxicity. Adverse effects include oral mucositis, dyslipidemia, fatigue and infections. In contrast, fast- flow malformations show negligible benefit, consistent with their distinct genetic architecture, which predominantly activates RAS/MAPK rather than PI3K/AKT/mTOR signalling.

Sirolimus is an effective targeted therapy for refractory slow- flow vascular malformations but should not be considered a universal treatment for all vascular anomalies. Future directions include molecularly guided therapy, rational combination regimens and integration with PI3K- and AKT- directed agents.